Several techniques for the production of microparticles containing biological or chemical agents by an emulsion-based manufacturing technique have been reported. In general, the methods have a first phase consisting of an organic solvent, a polymer and a biological or chemical agent dissolved or dispersed in the first solvent. The second phase comprises water and a stabilizer and, optionally, the first solvent. The first and the second phases are emulsified and, after an emulsion is formed, the first solvent is removed from the emulsion, producing hardened microparticles.
An alternative method involves the formation of a “double emulsion”. In this method, a first phase, often called an “internal phase”, is produced and normally consists of water, a biological or chemical agent, and, possibly, a stabilizer. A second-phase normally consists of an organic solvent and a polymer. The first and second phases are emulsified to form a water-in-oil “internal emulsion”. A third-phase usually consists of water, a surfactant and, optionally, the second solvent. The internal emulsion is then emulsified again with the third phase to form an oil-in-water “external emulsion”. After the external emulsion is formed, the organic solvent is removed from the emulsion, producing hardened microparticles.
Emulsions may be formed by a variety of techniques. One such technique is the use of a batch device for mixing the first and second phases under turbulent conditions such as with a stirrer as disclosed in U.S. Pat. No. 5,407,609. Other batch processes may employ a homogenizer or a sonicator. In another technique, an emulsion is formed by continuously mixing the first phase and second phase, in-line, using turbulent flow conditions, as in the use of an in-line dynamic mixer or an in-line static mixer such as described in U.S. Pat. No. 5,654,008.
When emulsions are created by a turbulent mixing device, such as static and dynamic mixers, a turbulent region exists where the two phases mix and the emulsion is formed. This mixing technique is problematic because turbulent mixers create areas of varying turbulence as some areas in the mixer produce a higher turbulence (typically closer to the blades and walls), while other areas produce lower turbulence (further away from blades and walls). Varying turbulence within the mixer results in a wide range of microparticle sizes, which can be undesirable.
Another problem with using turbulent mixing devices for producing microparticles is that a whole range of parameters such as flow rates, viscosities, densities, surface tension and temperature govern the level of turbulence inside the apparatus itself. The sensitivity of a turbulent process to the fluid flow and other physical properties makes it difficult to consistently produce a final product with the same properties. Batch to batch variation is not acceptable for the majority of microparticle products.
Another problem with turbulent mixing processes for the production of microparticles is that some active agents, such as proteins, are sensitive to high shear forces that are inherently part of turbulent mixing. Hence, these processes cannot be utilized to create microparticles with some common biological or chemical agents.
An additional difficulty with turbulent mixing processes relates to scalability. Turbulence, and the resulting microparticle properties, cannot be accurately predicted when changing the scale of production. This means that any time a change is made to the turbulent emulsion apparatus, a new set of experiments must be conducted in order to establish new guidelines for operation of the device in order to create the desired microparticle product. The need for repeated testing whenever scaling up production is expensive and time-consuming.
Turbulent-based emulsion devices also have physical limitations, specifically with their application of the laws of fluid dynamics. When using turbulent flow mixing devices, the dynamics of a particular mixer is correlated with a particular microparticle size and microparticle size distribution.
In order to achieve the same microparticle size and distribution when scaling up or scaling down, the same mixing turbulence must be produced in the larger or smaller mixer. As scaling up involves a change in the size of the mixer, a change in velocity (V) must be accomplished in order to compensate for the change in the diameter (D) of the mixer. Thus, application of a turbulent-based process for the formation of microparticles becomes especially difficult, and ultimately not practical, when very low flow rates are desirable because it is hard to achieve the desirable turbulence.
In the above-mentioned production processes, the resultant particle size is a function of the shear forces experienced by the two phases when mixed. Shear forces in these methods vary across the volume being mixed and, as a result, produce relatively broad particle size distributions. In the case of production processes dependent on turbulent flow, it is difficult to achieve turbulent flow conditions for low flow rates such as might be used during exploratory experiments with limited volumes, and the performance of larger devices is difficult to predict from results with small versions. Hence, there is little correlation between the results achieved on a small-scale in the laboratory and those achieved in later manufacture-sized production with turbulent flow based production processes.
An alternative method for producing an emulsion utilizes a packed bed emulsifier, as described in U.S. Pat. No. 4,183,681 ('681). The '681 patent describes the use of a packed bed emulsifier to form oil-in-water emulsions. Unfortunately, the emulsions disclosed do not form microparticles, are directed to applications with oil/water phase volume ratios equal to or greater than 1:1 and the packing materials that are found to be effective are not compatible with the need for clean and sterile apparatus such as required for microparticles containing therapeutic chemical or biological agents.
Other alternative emulsion forming techniques may employ filtration membranes or passage of fluids through a microchannel device as described in U.S. Pat. No. 6,281,254. These methods require precision fabrication and can be cumbersome to scale up to production volumes.
Thus, a method is needed for forming emulsion-based microparticles that provides a narrow, reproducible, particle size distribution, capable of use with both large and small volumes, and is capable of being conveniently scaled up while providing predictable emulsion properties. Ideally, this method would utilize a non-turbulent emulsifier in order to allow its use with all chemical or biological agents.